Liver resection has become an increasingly safe procedure, but certain procedures remain high-risk, such as massive liver resection (i.e., 70% or more) and small-for-size (SFS) liver transplantation (1-3). Massive hepatic resection is the only option for some patients with primary or secondary liver tumors. With regard to SFS transplantation, the use of partial liver grafts has the potential to significantly reduce the donor shortage by allowing the donor organ to be split between two recipients. In addition, living donor liver transplantation is emerging as an option for some patients, a procedure requiring liver resection and regeneration in the donor and regeneration in the recipient.
The failure of a partial liver to regenerate is considered a critical contributing factor in post-surgical primary liver dysfunction and liver failure, and minimal viable liver volume required for regeneration, following either massive liver resection or SFS transplantation, is an important concept (1-3). Impaired liver regeneration and liver dysfunction has been strongly linked to the extent of hepatic ischemia reperfusion injury (IRI), an unavoidable consequence of the surgical procedures, and studies in rodent models have shown that small liver fragments and SFS grafts are more susceptible to IRI (3-7). Although the precise mechanisms responsible for liver dysfunction and failure in small liver remnants and SFS grafts are not well understood, complement appears to play an important role in both IRI and liver regeneration.
Complement is an important component of immunity, but inappropriate and excessive activation of the complement system is involved in numerous pathological conditions, including IRI. Complement activation products that mediate tissue injury are generated at various points in the complement pathway. Complement activation on a cell surface results in the cleavage of serum C3 and the covalent attachment of C3 fragments that serve as opsonins for immune effector cells. C3 cleavage also results in the generation of C3a, a soluble peptide that is a potent anaphylatoxin. Later in the pathway, serum C5 is cleaved to release soluble C5a, another potent anaphylatoxin and chemoattractant with a wide range of bioactive properties. Cleavage of C5 also initiates formation of the membrane attack complex (MAC), a cytolytic protein complex that assembles in cell membranes, ultimately resulting in cell lysis.
The disclosures of all publications, protein or nucleic acid sequences, accession numbers referring to protein or nucleic acid sequences in public sequence databases, patent applications and patents cited in this specification are hereby incorporated herein by reference in their entirety, as if each individual publication, patent application, or patent were specifically and individually indicated to be incorporated by reference. In particular, all publications cited herein are expressly incorporated by reference for the purpose of describing and disclosing compositions and methodologies which might be used in connection with the invention. Although the invention described herein has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.